Novel Polylactide‐Based Release Systems for Local Antibiotic Therapies

Antibiotic delivery systems based on biodegradable polymers have found considerable interest for the local therapy of bone infections. In this study polylactide based polymer and composite delivery systems for the release of gentamicin have been fabricated from poly‐L‐lactides and a poly(L‐lactide‐co‐D,L‐lactide) as well as biodegradable inorganic fillers (calcium hydrogen phosphate, calcium sulfate dihydrate). The in vitro release profiles of the polymer delivery systems were characterized by an initial burst release followed by a sustained release of small gentamicin amounts up to 3 weeks. In the composite delivery systems a loss of retardation was observed with an increasing content of inorganic filler material. It was found that the in situ complex formation of gentamicin by adding defined amounts of sodium dodecyl sulfate represents a valuable tool to overcome this problem and to modulate the release profile of the delivery systems in a wide range. Under in vitro conditions, calcium sulfate dihydrate containing delivery systems are rapidly degraded in aqueous medium within several months. Based on these results, the developed composite delivery systems are promising candidates for the efficient treatment of bone infections.     

Controlled release of gentamicin from biomimetic calcium phosphate in vitro. Comparison of four different incorporation methods

Cylinders of biomimetic (nanocrystalline) calcium phosphate were loaded with gentamicin by four different methods: 1) dip‐coating, 2) impregnation followed by cold‐isostatic pressing, 3) co‐precipitation followed by cold‐isostatic pressing, and 4) coating of co‐precipitated particles with a biodegradable polymer PDLLA (poly‐D,L‐lactide), followed by uniaxial pressing. The release kinetics were studied in vitro over 10 days. The incorporation by methods 2), 3) and 4) showed a significantly higher long‐term release of active gentamicin than dip‐coating, although there was an initial burst during the first two days with all four methods. With method 4), there was an increase of the released gentamicin after 7 days, and the long‐term release was the highest of these four methods. The results are of considerable interest for the preparation of biodegradable bone implants which are loaded with biologically active substances.     

Novel fatty acid gentamicin salts as slow-release drug carrier systems for anti-infective protection of vascular biomaterials

Infections of vascular prostheses are still a major risk in surgery. The current work presents an in vitro evaluation of novel slow release antibiotic coatings based on new gentamicin fatty acid salts for polytetrafluoroethylene grafts. These grafts were coated with gentamicin sodium dodecyl sulfate, gentamicin laurate and gentamicin palmitate. Drug release kinetics, anti-infective characteristics, biocompatibility and haemocompatibility of developed coatings were compared to commercially available gelatin sealed PTFE grafts (SEALPTFE?) and knitted silver coated Dacron(?) grafts (InterGard(?)). Each gentamicin fatty acid coating showed a continuous drug release in the first eight hours followed by a low continuous release. Grafts coated with gentamicin fatty acids reduced bacterial growth even beyond pathologically relevant high concentrations. Cytotoxicity levels depending on drug formulation bringing up gentamicin palmitate as the most promising biocompatible coating. Thrombelastography studies, ELISA assays and an amidolytic substrate assay confirmed haemocompatibility of developed gentamicin fatty acid coatings comparable to commercially available grafts.     

Effect of the solubility of antibiotics on their release from degradable polyurethane

Application of biodegradable polyester urethane, as a drug loading matrix in the form of a coating on implant devices was investigated. Polyester urethane films were loaded with model antibiotics, like rifampicin, gentamicin and ciprofloxacin and their release characteristics were evaluated in simulated body fluid. Effect of solubility of antibiotics and degradation of matrix on the drug release behavior of biodegradable polyester urethane coating was also studied. It was observed that antibiotics having hydrophilicity or lipophilicity same as that of polymer matrix provide an extended release with relatively less initial burst release. Effect of degradation of polymer matrix has a dual significance in this case and the drug release rate increases with the increase in degradation rate. A high initial burst release was observed for antibiotics having hydrophilicity or lipophilicity opposite to that of polyurethane matrix and hence in this case antibiotic release was not significantly controlled by degradation of matrix.     

Study of Drug Release from Pellets Coated with Surelease Containing Hydroxypropylmethylcellulose

The release of metoclopramide hydrochloride (a very water soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with Surelease containing hydroxypropylmethylcellulose (HPMC) at different coating loads was investigated. The release rates of either drug at each coating composition decreased as the coating load increased. Inclusion of HPMC E15 increased the release rates of both drugs compared to pellets coated only with Surelease. This was thought to be due to the leakage of the soluble part of the film (HPMC E15) during dissolution, which left pores for drug release. The Surelease:HPMC E15 ratio had a major role in the release rates of drugs. Addition of HPMC E15 into Surelease did not change the release mechanism for metoclopramide hydrochloride (the mean value of n ≈ 0.57) from that of Surelease alone, and diffusion remained the main mechanism controlling the release. However, the release exponent (≈1.28) increased for diclofenac sodium on addition of HPMC E15, indicating a dissolutioncontrolled mechanism. Despite its lower water solubility, diclofenac sodium was released slightly faster than metoclopramide hydrochloride from pellets coated with Surelease containing HPMC E15 at equivalent coating loads.     

Antimicrobial activity of gentamicin palmitate against high concentrations of <Emphasis Type="Italic">Staphylococcus aureus</Emphasis>

The reduction of implant related infections plays a pivotal role in orthopaedic surgery as an increasing number of people require implants (up to 200,000 per year in the United States (source: Joint Implant Surgery & Research Foundation 2010)). The aim of the current study is to prevent and thus decrease the number of bacterial infections. Both pre and post operative systemic antibiotic treatment and gentamicin containing bone cements (polymethylmethacrylate, PMMA) are commonly used strategies to overcome infections. In this study, the antimicrobial efficacy of gentamicin sulfate loaded bone cement was compared with titan discs coated with a new form of gentamicin, gentamicin palmitate. Adherence prevention, killing rates and killing kinetics were compared in an in vitro model, using Staphylococcus aureus (S. aureus), which together with Staphylococcus epidermidis (S. epidermidis) represents 60% of bacteria found responsible for hip implant infections (An and Friedman, 1996, J Hosp Infect 33(2):93–108). In our experiments gentamicin, which was applied as gentamicin palmitate on the surface of the implants, showed a high efficacy in eliminating bacteria. In contrast to gentamicin sulfate containing bone cements, gentamicin palmitate is released over a shorter period of time thus not inducing antibiotic resistance. Another benefit for clinical application is that it achieves high local levels of active ingredient which fight early infections and minimize toxic side effects. Furthermore, the short term hydrophobic effect of gentamicin palmitate can successfully impede biofilm formation. Thus, the use of self-adhesive antibiotic fatty acid complexes like gentamicin palmitate represents a new option for the anti-infective coating of cementless titan implants.     

Latex Film Matrix Systems with a Concentration Gradient for Controlled Drug Delivery

Abstract

Latex film matrix systems with a nonuniform drug distribution were prepared by a coating process. In this process a drug concentration gradient in the coating dispersion was generated by the programmable pumping of the latex into a drug reservoir which contained the drug and latex. The film matrix formed by the dispersion would have a built-in drug concentration gradient as the coating process proceeded. A mathematical model was developed to describe the concentration change of the active ingredient in the coating dispersion as a function of the spraying rate of the coating dispersion, the pumping rate of the latex into the drug reservoir, and the initial drug concentration in the dispersion. The applicability of this process was demonstrated by the controlled in vitro dissolution of acetaminophen from ethylcellulose latex film matrices formed on glass beads. The release profile of the active ingredient from the systems changed as the drug concentration gradient profile in the matrix was altered, and a higher drug concentration gradient in the matrix resulted in a slower release rate and a more linear release profile. A faster drug release rate can also be achieved by incorporating a highly water soluble ingredient in the concentration gradient matrix.     

In vitro evaluation of gentamicin release from a bioactive tricalcium silicate bone cement

Tricalcium silicate (Ca₃SiO₅) cement, a novel self-setting biomaterial, has been shown to exhibit good hydraulic properties and excellent bioactivity. In this study, gentamicin sulfate (GS) was integrated into cement pastes and in vitro release of GS from the Ca₃SiO₅ cement was performed in deionized water, phosphate buffer saline (PBS) and HCl solutions with different pH at 37 °C, respectively. The results showed that the initial fast release of GS was restricted to a low level and prolonged release of drugs was achieved in water and PBS. The prolonged GS release is attributed to the interaction of GS with the calcium silicate hydrate network and the formation of unique nano-to-micro porous structure after hydration. Furthermore, GS release from milled powders of the hydrated cement suggested that the constrained GS could be released at low pH environment or during the degradation of the cement. When the samples were soaked in PBS, a nano-structured apatite layer was formed on the surface of the cement, which resulted in a relatively lower GS release rate as compared to that in water. The results suggest that Ca₃SiO₅ cement might be used as bioactive bone implant materials with drug loading and prolonged release properties.     

Heterocyclic methacrylate-based drug release polymer system

A heterocyclic methacrylate polymer system, developed originally as a low shrinkage polymer system, has been investigated as a drug release polymer and as a biomaterial for encouraging bone or cartilage regeneration. The system is based on poly (ethyl methacrylate) polymer powder mixed with tetrahydrofurfuryl methacrylate monomer and polymerized at room temperature (PEM/THFM). Promising results have been obtained with this biomaterial, and hence its water uptake properties were investigated in detall, in order to throw some light on the release processes that are involved in vivo and in vitro. Water soluble large molecule analogues were incorporated into the system; these additives increased the water uptake of the system. Isobornyl methacrylate was used as a diluent for the monomer to further reduce the water uptake of the system. In all cases the uptake kinetics did not obey simple diffusion theory, the process being very prolonged and complex.     

Study of Drug Release from Pellets Coated with Surelease Containing Hydroxypropylmethylcellulose

The release of metoclopramide hydrochloride (a very water soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with Surelease containing hydroxypropylmethylcellulose (HPMC) at different coating loads was investigated. The release rates of either drug at each coating composition decreased as the coating load increased. Inclusion of HPMC E15 increased the release rates of both drugs compared to pellets coated only with Surelease. This was thought to be due to the leakage of the soluble part of the film (HPMC E15) during dissolution, which left pores for drug release. The Surelease:HPMC E15 ratio had a major role in the release rates of drugs. Addition of HPMC E15 into Surelease did not change the release mechanism for metoclopramide hydrochloride (the mean value of n ≈ 0.57) from that of Surelease alone, and diffusion remained the main mechanism controlling the release. However, the release exponent (≈1.28) increased for diclofenac sodium on addition of HPMC E15, indicating a dissolutioncontrolled mechanism. Despite its lower water solubility, diclofenac sodium was released slightly faster than metoclopramide hydrochloride from pellets coated with Surelease containing HPMC E15 at equivalent coating loads.     

Biodegradable Antibacterial Polymeric Nanosystems: A New Hope to Cope with Multidrug‐Resistant Bacteria

The human society is faced with daunting threats from bacterial infections. Over decades, a variety of antibacterial polymeric nanosystems have exhibited great promise for the eradication of multidrug‐resistant bacteria and persistent biofilms by enhancing bacterial recognition and binding capabilities. In this Review, the “state‐of‐the‐art” biodegradable antibacterial polymeric nanosystems, which could respond to bacteria environments (e.g., acidity or bacterial enzymes) for controlled antibiotic release or multimodal antibacterial treatment, are summarized. The current antibacterial polymeric nanosystems can be categorized into antibiotic‐containing and intrinsic antibacterial nanosystems. The antibiotic‐containing polymeric nanosystems include antibiotic‐encapsulated nanocarriers (e.g., polymeric micelles, vesicles, nanogels) and antibiotic‐conjugated polymer nanosystems for the delivery of antibiotic drugs. On the other hand, the intrinsic antibacterial polymer nanosystems containing bactericidal moieties such as quaternary ammonium groups, phosphonium groups, polycations, antimicrobial peptides (AMPs), and their synthetic mimics, are also described. The biodegradability of the nanosystems can be rendered by the incorporation of labile chemical linkages, such as carbonate, ester, amide, and phosphoester bonds. The design and synthesis of the degradable polymeric building blocks and their fabrications into nanosystems are also explicated, together with their plausible action mechanisms and potential biomedical applications. The perspectives of the current research in this field are also described.     

Superparamagnetic Iron Oxide Nanoparticles (SPION) for the Treatment of Antibiotic‐Resistant Biofilms

Bacterial infections caused by antibiotic‐resistant strains are of deep concern due to an increasing prevalence, and are a major cause of morbidity in the United States of America. In particular, medical device failures, and thus human lives, are greatly impacted by infections, where the treatments required are further complicated by the tendency of pathogenic bacteria, such as Staphylococcus aureus, to produce antibiotic resistant biofilms. In this study, a panel of relevant antibiotics used clinically including penicillin, oxacillin, gentamicin, streptomycin, and vancomycin are tested, and although antibiotics are effective against free‐floating planktonic S. aureus, either no change in biofilm function is observed, or, more frequently, biofilm function is enhanced. As an alternative, superparamagnetic iron oxide nanoparticles (SPION) are synthesized through a two‐step process with dimercaptosuccinic acid as a chelator, followed by the conjugation of metals including iron, zinc, and silver; thus, the antibacterial properties of the metals are coupled to the superparamagnetic properties of SPION. SPION might be the ideal antibacterial treatment, with a superior ability to decrease multiple bacterial functions, target infections in a magnetic field, and had activity better than antibiotics or metal salts alone, as is required for the treatment of medical device infections for which no treatment exists today.     

Controlled Delivery of Gentamicin Antibiotic from Bioactive Electrospun Polylactide‐Based Ultrathin Fibers

The purpose of this study was to generate ultrathin fibers based on polylactide (PLA) biopolyester with antimicrobial controlled release capacity to treat bacterial infections. To achieve this objective, gentamicin antibiotic was encapsulated into pure PLA fibers, a blend of PLA–collagen and coaxial fibers containing a skin of PLA and a core of collagen using the electrospinning technique. The morphology of the gentamicin‐loaded fibers and the antibiotic distribution within the fibers were examined by SEM and TEM. The drug delivery profile of the different electrospun fibers was analyzed using a spectrophotometric method. The performance for treating common possible post‐surgical infections was investigated against Staphylococcus epidermis, Pseudomonas aeruginosa and Escherichia coli. The morphology of the electrospun fibers as well as the hydrophilicity of the polymer blends ultimately determined the antibiotic release characteristics. The results indicated that such drug‐loaded fibers can serve as advanced delivery platforms with strong and timing controllable antibacterial properties.     

The effect of storage temperatures on the in vitro properties of a polyanhydride implant containing gentamicin

Septacin® is a biodegradable sustained-release implant containing 20% (w/w) gentamicin sulfate. The matrix of the implant is a polyanhydride copolymer composed of erucic acid dimer (EAD) and sebacic acid (SA) in a one-to-one weight ratio. The effect of storage temperatures (-15°C and 25°C) on the stability of Septacin® was evaluated with respect to gentamicin potency, copolymer molecular weight, and in vitro drug release. The drug in polymer matrix was stable for at least 12 months when stored at 25°C, but the molecular weight of the copolymer declined rapidly at this temperature. At -15°C, there was no change in the molecular weight of the copolymer. However, the placebo (copolymer without gentamicin) exhibited a significant drop in copolymer molecular weight at both temperatures. The drug release profiles showed no change for samples stored at -15°C for the duration of this study, while the release of drug slowed down significantly for samples stored at 25°C for longer than one month. A pronounced difference in the morphology of the -15°C samples and the 25°C samples was observed during the in vitro dissolution test; cracking of the -15°C samples was evident, but the 25°C samples remained intact.     

Comparative study of drug release from pellets coated with HPMC or Surelease

The release of metoclopramide hydrochloride (very water soluble cationic drug) and diclofenac sodium (sparingly soluble anionic drug) from pellets coated with hydroxypropylmethylcellulose (HPMC; water-soluble polymer) or ethylcellulose aqueous dispersion (Surelease; water-insoluble polymer) at different coating loads was investigated. The release rates of either drug decreased as the coating load of HPMC increased, but overall, the release was fast, and the majority of both drugs released in about 1 hr, even at the highest coating load. The drug release mechanism for either drug was not affected by the coating load of HPMC or by the type of drug used, and it was found to be mainly diffusion controlled. Diclofenac sodium released slightly more slowly than metoclopramide hydrochloride from HPMC-coated pellets. This was attributed to the lower water solubility of the former drug. The release rate of either drug decreased greatly as the coating load of Surelease increased. The release of both drugs was sustained over 12 hr as the coating load of Surelease increased, and only about 70% of either drug was released after this period at the highest coating load (20%). The mechanism of release of metoclopramide hydrochloride was independent of coating load, and it was predominantly diffusion controlled. However, the mechanism of diclofenac sodium release was dependent on the coating load of Surelease. At low coating loads, diffusion of drug was facilitated due to the presence of more pores at the surface of the coated pellets; therefore, the rate of dissolution of the drug particles was the rate-limiting step. However, at high coating loads, drug release was mainly diffusion controlled. Despite its lower water solubility, diclofenac sodium released slightly faster than metoclopramide hydrochloride from Surelease-coated pellets at equivalent coating loads.     

Dissolution behaviour of plasma sprayed apatite coatings

Understanding the interaction of bioactive coatings with aqueous media is essential for development of systems possessing rapid osteointegration and durability. An in vitro study of a commercial, plasma sprayed hydroxyapatite coating has been undertaken. The coating behaviour when test coupons were immersed in water, simulated body fluid and foetal calf serum has been examined. The principal aim was to characterise, in detail, any structural changes to the coatings and, in particular, examine features of any new layers formed. The amorphous phase of the coating showed preferential dissolution in all media. The rate of dissolution was greatest in water and the process was initially retarded in the foetal calf serum. A nanocrystallite apatite layer was shown to precipitate on the coatings in all media although this was significantly enhanced in simulated body fluid. The features of this layer (e.g., lattice parameters, crystallite size etc.) were quantified by adopting a novel approach to the X-ray diffraction data analysis. The results are discussed in the context of similar studies and implications for in vivo behaviour.     

Drug loading and release of Tobramycin from hydroxyapatite coated fixation pins

This paper evaluates the loading and release properties of Tobramycin incorporated by adsorptive loading from a solution into plasma sprayed and biomimetically coated Hydroxyapatite (HA) fixation pins. The aim of this study is to contribute towards designing a functional implant surface offering local release of the antibiotic agent to prevent post-surgical infections. Cathodic arc deposition is used to coat stainless steel fixation pins with a bioactive, anatase phase dominated, TiO₂ coating onto which a HA layer is grown biomimetically. The loading and release properties are evaluated by studying the subsequent release of Tobramycin using high performance liquid chromatography and correlated to the differences in HA coating microstructure and the physical conditions under loading. The results from these studies show that a dual loading strategy consisting of a solution temperature of 90 °C and a pressure of 6 bar during a loading time of 5 min release a sufficient amount of Tobramycin to guarantee the inhibition of Staphylococcus aureus up to 2 days for plasma sprayed HA coatings and for 8 days for biomimetic coatings. The present study emphasizes the advantages of the nanoporous structure of biomimetically deposited HA over the more dense structure of plasma sprayed HA coatings in terms of antibiotic incorporation and subsequent sustained release and provides a valuable outline for the design of implant surfaces aiming for a fast-loading and controlled, local drug administration.     

A new concept of gentamicin loaded HAP/TCP bone substitute for prophylactic action: in vitro release validation

Infections and their consequences are a considerable problem in orthopaedic surgery. Despite intravenous prophylactic antibiotic administration, infection rates can reach in some occasions more than 1%. Indeed, the concentration in bone tissues is very low with the majority of antibiotics. Because high local dose can be obtained, the local release of gentamicin from acrylic bone cements has been shown to be efficient in preventing infections. However, for surgical procedures other than cemented prostheses no other local antibiotic releasing device is clinically available. The purpose of this study was to validate the concept of a gentamicin loaded bone substitute. About 125 mg of gentamicin were introduced into a HAP/TCP bone substitute for prophylactic purpose, to enhance the efficiency of systemic antibiotic treatments. The release rate of gentamicin from the bone substitute was investigated in vitro, in 0.9% sodium chloride solution. The rate appeared to be related to the bone substitute volume. All the gentamicin was released in less than 48 h. This release rate corresponds to the recommendations for the prophylactic use of antibiotics: the duration of the treatment should be less than 48 h, not to select antibiotic-resistant bacterial strains.     

Recent Trends and Progress in Sustained or Controlled Oral Delivery of Some Water Soluble Drugs: Morphine Salts, Diltiazem and Captopril

The development of oral controlled release systems has been a challenge to formulation scientists due to their inability to restrain and localise the system at targeted areas of the gastrointestinal (GI) tract. Controlled/sustained release preparations using alternative routes have been formulated but the oral route still remains the most desirable. For obvious reason, water soluble drugs are more difficult to deliver orally in sustained or controlled release manner than lipophilic drugs. Attempts have been made to regulate the release process by incorporating hydrophobic fillers within the system or by coating the drug with poorly soluble, swollen or non-swollen polymers or other substances. Others used the so called 'hydrodynamically balanced systems' which float in the gastric fluid at the stomach thereby increase the residence time for the device in the GI tract. A new approach has been the use of mucoadhesive systems to increase the residence time of the device within the GI tract. This review focuses on the progress made in the design of controlled/sustained release delivery systems for some water soluble drugs. Highly/freely water soluble diltiazem, captopril and morphine salts have been selected as model drugs due to the leading role they play in their respective field of therapy and their widespread use in treating chronic patients. Particular emphasis is given to delivery systems designed to achieve their once a day dose treatment.     

A Diffusion Controlled Drug Delivery System for Theophylline

Abstract

The goal of achieving ideal attributes of a drug delivery system including reliability and predictability has led investigators to design controlled release (CR) systems based on the principles of microporous coatings, diffusion controlled coatings and various hydrogel type systems.

In this study, the critical role of “water content fraction” of a polymer in deciding its diffusion characteristics has been ascertained and the correlation between molecular size/shape, membrane thickness, pore radii and drug diffusion has also been demonstrated. The theoretical considerations, designing and engineering of a “barrier coated-reservoir” type of a delivery system for theophylline using poly (vinyl alcohol) [PVA] as the coating material are discussed. After realizing the desired theoretical in-vitro release profile, in-vivo studies were carried out on a dog model. The potential of poly (vinyl alcohol) as a barrier coating material in developing a CR system is interestingly observed.